Publications by authors named "Rui Kong"

105 Publications

PPAR-Alpha Agonist Fenofibrate Combined with Octreotide Acetate in the Treatment of Acute Hyperlipidemia Pancreatitis.

PPAR Res 2021 20;2021:6629455. Epub 2021 Apr 20.

Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.

At present, there are more and more patients with acute hypertriglyceridemia pancreatitis in clinical practice. Common treatment measures include fasting and water withdrawal, fluid resuscitation, and somatostatin. In recent years, studies have pointed out that the PPARa agonist fenofibrate may help improve the condition of such patients. Therefore, through clinical research and analysis, we reported for the first time that fenofibrate combined with octreotide acetate has a more excellent effect in the treatment of patients with acute hypertriglyceridemia pancreatitis, and from the perspective of signal pathways, we revealed that the combination of the two drugs has an effect on NF-B P65. The synergistic inhibitory effect proves that the combined treatment is beneficial to control inflammation, protect liver function, and improve the prognosis of patients. It is worthy of clinical promotion.
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http://dx.doi.org/10.1155/2021/6629455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081610PMC
April 2021

Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2A.

PPAR Res 2021 16;2021:6663782. Epub 2021 Apr 16.

Department of Gastroenterology, Shanghai Tenth People's Hospital Affiliated to Tongji University, Tongji University, School of Medicine, Shanghai 200072, China.

Peroxisome proliferator-activated receptor alpha (PPARA) is the molecular target of fibrates commonly used to treat dyslipidemia and diabetes. Recently, the potential role of PPARA in other pathological conditions, such as cancers, has been recognized. Here, using bioinformatics analysis, we found that PPARA was expressed at relatively low levels in pancancers, and Kaplan-Meier analyses revealed that high PPARA protein expression was correlated with better survival of patients with colon cancer. experiments showed that fenofibrate regulated cell cycle distribution, promoted apoptosis, and suppressed cell proliferation and epithelial mesenchymal transition by activating PPARA. PPARA activation inhibited DNMT1 activity and abolished methylation-mediated CDKN2A repression. Downregulation of cyclin-CDK complexes led to the restoration of CDKN2A, which caused cell cycle arrest in the G1 phase via regulation of the CDKN2A/RB/E2F pathway. Finally, we demonstrated that fenofibrate administration inhibited tumor growth and DNMT1 activity . The PPARA agonist, fenofibrate, might serve as an applicable agent for epigenetic therapy of colon cancer patients.
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http://dx.doi.org/10.1155/2021/6663782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075693PMC
April 2021

Mutational fitness landscapes reveal genetic and structural improvement pathways for a vaccine-elicited HIV-1 broadly neutralizing antibody.

Proc Natl Acad Sci U S A 2021 Mar;118(10)

Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66045;

Vaccine-based elicitation of broadly neutralizing antibodies holds great promise for preventing HIV-1 transmission. However, the key biophysical markers of improved antibody recognition remain uncertain in the diverse landscape of potential antibody mutation pathways, and a more complete understanding of anti-HIV-1 fusion peptide (FP) antibody development will accelerate rational vaccine designs. Here we survey the mutational landscape of the vaccine-elicited anti-FP antibody, vFP16.02, to determine the genetic, structural, and functional features associated with antibody improvement or fitness. Using site-saturation mutagenesis and yeast display functional screening, we found that 1% of possible single mutations improved HIV-1 envelope trimer (Env) affinity, but generally comprised rare somatic hypermutations that may not arise frequently in vivo. We observed that many single mutations in the vFP16.02 Fab could enhance affinity >1,000-fold against soluble FP, although affinity improvements against the HIV-1 trimer were more measured and rare. The most potent variants enhanced affinity to both soluble FP and Env, had mutations concentrated in antibody framework regions, and achieved up to 37% neutralization breadth compared to 28% neutralization of the template antibody. Altered heavy- and light-chain interface angles and conformational dynamics, as well as reduced Fab thermal stability, were associated with improved HIV-1 neutralization breadth and potency. We also observed parallel sets of mutations that enhanced viral neutralization through similar structural mechanisms. These data provide a quantitative understanding of the mutational landscape for vaccine-elicited FP-directed broadly neutralizing antibody and demonstrate that numerous antigen-distal framework mutations can improve antibody function by enhancing affinity simultaneously toward HIV-1 Env and FP.
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http://dx.doi.org/10.1073/pnas.2011653118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958426PMC
March 2021

Invadopodia: A potential target for pancreatic cancer therapy.

Crit Rev Oncol Hematol 2021 Mar 20;159:103236. Epub 2021 Jan 20.

Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address:

Dissemination of cancer cells is an intricate multistep process that represents the most deadly aspect of cancer. Cancer cells form F-actin-rich protrusions known as invadopodia to invade surrounding tissues, blood vessels and lymphatics. A number of studies have demonstrated the significant roles of invadopodia in cancer. Therefore, the specific cells and molecules involved in invadopodia activity can provide as therapeutic targets. In this review, we included a thorough overview of studies in invadopodia and discussed their functions in cancer metastasis. We then presented the specific cells and molecules involved in invadopodia activity in pancreatic cancer and analyzed their suitability to be effective therapeutic targets. Currently, drugs targeting invadopodia and relevant clinical trials are negligible. Here, we highlighted the significance of potential drugs and discussed future obstacles in implementing clinical trials. This review presents a new perspective on invadopodia-induced pancreatic cancer metastasis and may prosper the development of targeted therapeutics against pancreatic cancer.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103236DOI Listing
March 2021

Minimization of Entropy Generation Rate in Hydrogen Iodide Decomposition Reactor Heated by High-Temperature Helium.

Entropy (Basel) 2021 Jan 8;23(1). Epub 2021 Jan 8.

Institute of Thermal Science and Power Engineering, Wuhan Institute of Technology, Wuhan 430205, China.

The thermochemical sulfur-iodine cycle is a potential method for hydrogen production, and the hydrogen iodide (HI) decomposition is the key step to determine the efficiency of hydrogen production in the cycle. To further reduce the irreversibility of various transmission processes in the HI decomposition reaction, a one-dimensional plug flow model of HI decomposition tubular reactor is established, and performance optimization with entropy generate rate minimization (EGRM) in the decomposition reaction system as an optimization goal based on finite-time thermodynamics is carried out. The reference reactor is heated counter-currently by high-temperature helium gas, the optimal reactor and the modified reactor are designed based on the reference reactor design parameters. With the EGRM as the optimization goal, the optimal control method is used to solve the optimal configuration of the reactor under the condition that both the reactant inlet state and hydrogen production rate are fixed, and the optimal value of total EGR in the reactor is reduced by 13.3% compared with the reference value. The reference reactor is improved on the basis of the total EGR in the optimal reactor, two modified reactors with increased length are designed under the condition of changing the helium inlet state. The total EGR of the two modified reactors are the same as that of the optimal reactor, which are realized by decreasing the helium inlet temperature and helium inlet flow rate, respectively. The results show that the EGR of heat transfer accounts for a large proportion, and the decrease of total EGR is mainly caused by reducing heat transfer irreversibility. The local total EGR of the optimal reactor distribution is more uniform, which approximately confirms the principle of equipartition of entropy production. The EGR distributions of the modified reactors are similar to that of the reference reactor, but the reactor length increases significantly, bringing a relatively large pressure drop. The research results have certain guiding significance to the optimum design of HI decomposition reactors.
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http://dx.doi.org/10.3390/e23010082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828003PMC
January 2021

Virus-Like Particle Based Vaccines Elicit Neutralizing Antibodies against the HIV-1 Fusion Peptide.

Vaccines (Basel) 2020 Dec 15;8(4). Epub 2020 Dec 15.

Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA.

Broadly neutralizing antibodies (bnAbs) isolated from HIV-infected individuals delineate vulnerable sites on the HIV envelope glycoprotein that are potential vaccine targets. A linear epitope within the N-terminal region of the HIV-1 fusion peptide (FP8) is the primary target of VRC34.01, a bnAb that neutralizes ~50% of primary HIV isolates. FP8 has attracted attention as a potential HIV vaccine target because it is a simple linear epitope. Here, platform technologies based on RNA bacteriophage virus-like particles (VLPs) were used to develop multivalent vaccines targeting the FP8 epitope. Both recombinant MS2 VLPs displaying the FP8 peptide and Qβ VLPs displaying chemically conjugated FP8 peptide induced high titers of FP8-specific antibodies in mice. Moreover, a heterologous prime-boost-boost regimen employing the two FP8-VLP vaccines and native envelope trimer was the most effective approach for eliciting HIV-1 neutralizing antibodies. Given the potent immunogenicity of VLP-based vaccines, this vaccination strategy-inspired by bnAb-guided epitope mapping, VLP bioengineering, and prime-boost immunization approaches-may be a useful strategy for eliciting bnAb responses against HIV.
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http://dx.doi.org/10.3390/vaccines8040765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765226PMC
December 2020

Wnt/β-catenin signalling controls bile duct regeneration by regulating differentiation of ductular reaction cells.

J Cell Mol Med 2020 12 30;24(23):14050-14058. Epub 2020 Oct 30.

Department of Gastroenterology, Shanghai Tenth People's Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai, China.

Recently, the incidence of bile duct-related diseases continues to increase, and there is no effective drug treatment except liver transplantation. However, due to the limited liver source and expensive donations, clinical application is often limited. Although current studies have shown that ductular reaction cells (DRCs) reside in the vicinity of peribiliary glands can differentiate into cholangiocytes and would be an effective alternative to liver transplantation, the role and mechanism of DRCs in cholangiole physiology and bile duct injury remain unclear. A 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-enriched diet was used to stimulate DRCs proliferation. Our research suggests DRCs are a type of intermediate stem cells with proliferative potential that exist in the bile duct injury. Meanwhile, DRCs have bidirectional differentiation potential, which can differentiate into hepatocytes and cholangiocytes. Furthermore, we found DRCs highly express Lgr5, and Lgr5 is a molecular marker for neonatal DRCs (P < .05). Finally, we confirmed Wnt/β-catenin signalling achieves bile duct regeneration by regulating the expression of Lgr5 genes in DRCs (P < .05). We described the regenerative potential of DRCs and reveal opportunities and source for the treatment of cholestatic liver diseases.
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http://dx.doi.org/10.1111/jcmm.16017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754022PMC
December 2020

Correction: Gut microbiota patterns associated with somatostatin in patients undergoing pancreaticoduodenectomy: a prospective study.

Cell Death Discov 2020 15;6:105. Epub 2020 Oct 15.

Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang China.

[This corrects the article DOI: 10.1038/s41420-020-00329-4.].
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http://dx.doi.org/10.1038/s41420-020-00339-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562950PMC
October 2020

Gut microbiota patterns associated with somatostatin in patients undergoing pancreaticoduodenectomy: a prospective study.

Cell Death Discov 2020 28;6:94. Epub 2020 Sep 28.

Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang China.

Postoperative pancreatic fistula (POPF) is a common and dreaded complication after pancreaticoduodenectomy (PD). The gut microbiota has been considered as an crucial mediator of postoperative complications, however, the precise roles of gut microbiota in POPF are unclear. A prospective study was developed to explore the effects of somatostatin on gut microbiota and we aim to identify the microbial alterations in the process of POPF. A total of 45 patients were randomly divided into PD group or additional somatostatin therapy group. The fecal sample of each patient was collected preoperatively and postoperatively and the gut microbiota was analyzed by 16S rRNA sequencing. Our study found that somatostatin therapy was independent risk factor for the occurrence of POPF, and it reduced the microbial diversity and richness in patients. At genus level, somatostatin therapy led to a decreased abundance in Bifidobacterium, Subdoligranulum and Dubosiella, whereas the abundance of Akkermansia, Enterococcus and Enterobacter were increased. The abundance levels of certain bacteria in the gut microbiota have significantly shifted in patients with POPF. The LEfSe analysis revealed that Ruminococcaceae could be used as microbial markers for distinguishing patients with high risk of POPF. Furthermore, Verrucomicrobia and Akkermansia could be used as preoperative biomarkers for identifying patients without POPF. Our prospective study highlights the specific communities related with somatostatin therapy and discovers POPF-associated microbial marker, which suggests that gut microbiota may become a diagnostic biomarker and potential therapeutic target for POPF.
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http://dx.doi.org/10.1038/s41420-020-00329-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522245PMC
September 2020

Pain Relief during Oocyte Retrieval by Transcutaneous Electrical Acupoint Stimulation: A Single-Blinded, Randomized, Controlled Multicenter Trial.

Evid Based Complement Alternat Med 2020 22;2020:3285648. Epub 2020 Sep 22.

Center of Reproductive Medicine, The Second Hospital Affiliated to Shandong University of Traditional Chinese Medicine, Jinan, China.

Acupuncture has pain-relief effects, but no data were available on the use of transcutaneous electric acupoint stimulation (TEAS) in pain relief during oocyte retrieval. This study was designed to examine the effect of TEAS for pain relief in women undergoing transvaginal ultrasound-guided oocyte aspiration. This single-blinded, multicenter, randomized controlled trial was performed in China between May 2013 and May 2015. The subjects were randomized to mock TEAS and TEAS. TEAS or mock TEAS was administered 30 min before oocyte retrieval until the end of the operation. The primary and secondary endpoints were the pain measured using the visual analog scale (VAS) within 1 min and 1 hour after oocyte retrieval, respectively. Serum -endorphin levels were tested in the first 50 patients/group. 390 women were undergoing oocyte retrieval. Pain levels evaluated using VAS within 1 min (18.6 ± 1.3 vs. 24.4 ± 1.7, < 0.01) and 1 h after oocyte aspiration (4.6 ± 0.7 vs. 6.8 ± 0.8, < 0.05) were lower in the TEAS group than in the mock TEAS group. Nausea assessment revealed a significantly lower VAS score in the TEAS group within 1 min (1.2 ± 0.4 vs. 2.9 ± 0.7, < 0.033). Serum -endorphin levels were significantly higher in the TEAS group than in the mock TEAS group (11.4 ± 0.5 vs. 9.1 ± 0.4, < 0.001) after retrieval. Serum -endorphin levels were higher in the TEAS group after the procedure than baseline (11.4 ± 0.5 vs. 9.1 ± 0.3, < 0.001). Oocyte retrieval causes pain and discomfort, but TEAS is effective and safe for suppressing the pain and alleviating nausea associated with the operation.
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http://dx.doi.org/10.1155/2020/3285648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530499PMC
September 2020

Immune Monitoring Reveals Fusion Peptide Priming to Imprint Cross-Clade HIV-Neutralizing Responses with a Characteristic Early B Cell Signature.

Cell Rep 2020 08;32(5):107981

Vaccine Research Center, National Institutes of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA.

The HIV fusion peptide (FP) is a promising vaccine target. FP-directed monoclonal antibodies from vaccinated macaques have been identified that neutralize up to ∼60% of HIV strains; these vaccinations, however, have involved ∼1 year with an extended neutralization-eclipse phase without measurable serum neutralization. Here, in 32 macaques, we test seven vaccination regimens, each comprising multiple immunizations of FP-carrier conjugates and HIV envelope (Env) trimers. Comparisons of vaccine regimens reveal FP-carrier conjugates to imprint cross-clade neutralizing responses and a cocktail of FP conjugate and Env trimer to elicit the earliest broad responses. We identify a signature, appearing as early as week 6 and involving the frequency of B cells recognizing both FP and Env trimer, predictive of vaccine-elicited breadth ∼1 year later. Immune monitoring of B cells in response to vaccination can thus enable vaccine insights even in the absence of serum neutralization, here identifying FP imprinting, cocktail approach, and early signature as means to improve FP-directed vaccine responses.
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http://dx.doi.org/10.1016/j.celrep.2020.107981DOI Listing
August 2020

Prediction of High-Risk Types of Human Papillomaviruses Using Reduced Amino Acid Modes.

Comput Math Methods Med 2020 18;2020:5325304. Epub 2020 Jun 18.

College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, China.

A human papillomavirus type plays an important role in the early diagnosis of cervical cancer. Most of the prediction methods use protein sequence and structure information, but the reduced amino acid modes have not been used until now. In this paper, we introduced the modes of reduced amino acids to predict high-risk HPV. We first reduced 20 amino acids into several nonoverlapping groups and calculated their structure and physicochemical modes for high-risk HPV prediction, which was tested and compared with the existing methods on 68 samples of known HPV types. The experiment result indicates that the proposed method achieved better performance with an accuracy of 96.49%, indicating that the reduced amino acid modes might be used to improve the prediction of high-risk HPV types.
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http://dx.doi.org/10.1155/2020/5325304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320279PMC
May 2021

Identification of prognostic and metastasis-related alternative splicing signatures in hepatocellular carcinoma.

Biosci Rep 2020 07;40(7)

Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, China.

As the most common neoplasm in digestive system, hepatocellular carcinoma (HCC) is one of the most important leading cause of cancer deaths worldwide. Its high-frequency metastasis and relapse rate lead to the poor survival of HCC patients. However, the mechanism of HCC metastasis is still unclear. Alternative splicing events (ASEs) have a great effect in cancer development, progression and metastasis. We downloaded RNA sequencing and seven types of ASEs data of HCC samples, in order to explore the mechanism of ASEs underlying tumorigenesis and metastasis of HCC. The data were taken from the The Cancer Genome Atlas (TCGA) and TCGASpliceSeq databases. Univariate Cox regression analysis was used to determine a total of 3197 overall survival-related ASEs (OS-SEs). And based on five OS-SEs screened by Lasso regression, we constructed a prediction model with the Area Under Curve of 0.765. With a good reliability of the model, the risk score was also proved to be an independent predictor. Among identified 390 candidate SFs, Y-box protein 3 (YBX3) was significantly correlated with OS and metastasis. Among 177 ASEs, ATP-binding cassette subfamily A member 6 (ABCA6)-43162-AT and PLIN5-46808-AT were identified both associated with OS, bone metastasis and co-expressed with SFs. Then we identified primary bile acid biosynthesis as survival-related (KEGG) pathway by Gene Set Variation Analysis (GSVA) and univariate regression analysis, which was correlated with ABCA6-43162-AT and PLIN5-46808-AT. Finally, we proposed that ABCA6-43162-AT and PLIN5-46808-AT may contribute to HCC poor prognosis and metastasis under the regulation of aberrant YBX3 through the pathway of primary bile acid biosynthesis.
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http://dx.doi.org/10.1042/BSR20201001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364508PMC
July 2020

The outbreak of coronavirus disease in China: Risk perceptions, knowledge, and information sources among prenatal and postnatal women.

Women Birth 2021 May 29;34(3):212-218. Epub 2020 May 29.

Department of Nursing, Sir Run Run Hospital of Nanjing Medical University, PR China. Electronic address:

Background: The COVID-19 pandemic has created anxiety among members of the public, including all women over the childbirth continuum, who are considered to be at a greater risk of contracting most infectious diseases. Understanding the perspectives of health care consumers on COVID-19 will play a crucial role in the development of effective risk communication strategies. This study aimed to examine COVID-19-related risk perceptions, knowledge, and information sources among prenatal and postnatal Chinese women during the initial phase of the COVID-19 pandemic.

Methods: A cross-sectional survey design was adopted, and a four-section online questionnaire was used to collect data. Using a social media platform, the online survey was administered to 161 participants during the outbreak of COVID-19 in Nanjing, China, in February 2020.

Results: The participants perceived their risk of contracting and dying from COVID-19 to be lower than their risk of contracting influenza, however many of them were worried that they might contract COVID-19. The participants demonstrated adequate knowledge about COVID-19. The three major sources from which they obtained information about COVID-19 were doctors, nurses/midwives, and the television, and they placed a high level of confidence in these sources. There was no significant relationship between the perceived risk of contracting COVID-19 and knowledge about this disease.

Conclusion: The present findings offer valuable insights to healthcare professionals, including midwives, who serve on the frontline and provide care to pregnant women. Although the participants were adequately knowledgeable about COVID-19, they had misunderstood some of the recommendations of the World Health Organisation.
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http://dx.doi.org/10.1016/j.wombi.2020.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256526PMC
May 2021

Kidney-bean () Dependent, Exercise-induced Anaphylaxis in Patients Comorbid with Mugwort () Pollinosis.

Authors:
Rui Kong Jia Yin

Immunol Invest 2021 May 8;50(4):389-398. Epub 2020 Jun 8.

Department of Allergy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

: The cross-reactive allergen between mugwort () and kidney bean () has not yet been identified.: A total of 24 patients were included in this study. The sera of patients were analyzed for the concentrations of specific IgE antibodies. The allergenicity and cross-reactivity were investigated by Western blotting and immunoblot inhibitory experiments.: The immunoblotting indicated the binding of patients' IgE to crude mugwort extract at ~26 kDa protein (15 cases), ~60 kDa (15 cases), and 10-15 kDa proteins (12 cases). The results of the immunoblot-inhibition assay showed that kidney bean seed extract inhibited specific IgE binding to mugwort at 10-15 kDa, ~26 kDa, and ~60 kDa in 4 (16.7%), 1 (4.2%) and 2 (8.3%) cases, respectively. On the other hand, mugwort extract was demonstrated to inhibit specific IgE binding to kidney bean seed at 10-15 kDa, 15-20 kDa, ~30 kDa, and 60 kDa in 1 (4.2%), 3 (12.5%), 4 (16.7%), and 3 (12.5%) cases, respectively.: The 26-30 kDa, 10-15 kDa, and 60 kDa proteins are potential causative agents of the cross-reactivity between mugwort and kidney beans. The findings of this study improved the current understanding on the allergenicity of kidney beans and would provide insights into the refinement of treatment strategy for anaphylaxis.
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http://dx.doi.org/10.1080/08820139.2020.1770783DOI Listing
May 2021

Small Molecule Inhibitor C188-9 Synergistically Enhances the Demethylated Activity of Low-Dose 5-Aza-2'-Deoxycytidine Against Pancreatic Cancer.

Front Oncol 2020 8;10:612. Epub 2020 May 8.

Department of Pancreatic and Biliary Surgery, First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China.

Aberrant DNA methylation, especially hypermethylation of tumor suppressor genes, has been associated with many cancers' progression. 5-Aza-2'-deoxycytidine (DAC) can reverse hypermethylation-induced gene silencing via regulating DNA methyltransferases (DNMTs) activity, In addition, low-dose of DAC was proved to exert durable antitumor effects against solid tumor cells. Nevertheless, no clinical effect of DAC has been made when fighting against pancreatic cancer. Hence, it is necessary to raise a novel therapeutic strategy that further enhance the efficacy of DAC but not increase side effect, which impede the utilization of DAC. In the present study, we have discovered that C188-9, a novel signal transduction activator of transcription (STAT) inhibitor, could improve the antitumor effects of low-dose DAC and . Further study demonstrated that such improvement was attributed to re-expression of Ras association domain family member 1A (RASSF1A), a well-known tumor suppressor gene. Bisulfite sequencing PCR (BSP) assay showed that C188-9 combined with DAC treatment could significantly reverse the hypermethylation status of RASSF1A promoter, which indicated that C188-9 could enhance the demethylation efficacy of DAC. Our data demonstrated that DNA methyltransferase 1 (DNMT1) was the underlying mechanism that C188-9 regulates the demethylation efficacy of DAC. Overall, these findings provide a novel therapeutic strategy combining low-dose DAC and C188-9 to improve therapeutic efficacy by inhibiting DNMT1-inducing promoter methylation.
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http://dx.doi.org/10.3389/fonc.2020.00612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225308PMC
May 2020

Circular RNA hsa_circ_0085131 is involved in cisplatin-resistance of non-small-cell lung cancer cells by regulating autophagy.

Authors:
Rui Kong

Cell Biol Int 2020 Sep 19;44(9):1945-1956. Epub 2020 Jun 19.

Department of Oncology, The Third Affiliated Hospital of ChongQing Medical University, Chongqing, China.

Non-small-cell lung carcinoma (NSCLC) continues to top the list of cancer mortalities worldwide. The role of circular RNAs (circRNAs) in tumorigenesis has been increasingly appreciated, although it is relatively unexplored in NSCLC. Herein, we reported the role of hsa_circ_0085131 in NSCLC. In the present study, NSCLC tumor specimens exhibited a higher hsa_circ_0085131 level in comparison to para-tumor samples. And the higher level of hsa_circ_0085131 was associated with recurrence and poorer survival of NSCLC. Moreover, hsa_circ_0085131 promoted cell proliferation and cisplatin (DDP)-resistance. Furthermore, hsa_circ_0085131 regulated cell DDP-resistance by modulating autophagy. Hsa_circ_0085131 acted as a competing endogenous RNA of miR-654-5p to release autophagy-associated factor ATG7 expression, thereby promoting cell chemoresistance. In conclusion, hsa_circ_0085131 enhances DDP-resistance of NSCLC cells through sequestering miR-654-5p to upregulate ATG7, leading to cell autophagy. Therefore, these findings advocate targeting the hsa_circ_0085131/miR-654-5p/ATG7 axis as a potential therapeutic option for patients with NSCLC who are resistant to DDP.
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http://dx.doi.org/10.1002/cbin.11401DOI Listing
September 2020

Aberrant β-catenin Activity in Hepatoid Adenocarcinoma of the Stomach

Curr Mol Med 2020 05 22. Epub 2020 May 22.

Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072. China.

Background: Hepatoid adenocarcinoma of the stomach (HAS) has been recognized as a rare primary gastric tumor characterized by hepatocellular carcinomalike histology. HAS often causes diagnostic confusion with conventional gastric adenocarcinoma (CGA) due to the difficulty to detect hepatoid differentiation solely based on findings from hematoxylin and eosin (H&E) staining. β-catenin is highly expressed in hepatocellular carcinoma (HCC), which is involved in the maintenance of tumor initiating cells, drug resistance, tumor progression, and metastasis. Due to the scarcity of confirmed cases of HAS, there are few studies on β-catenin.

Objective: 14 patients diagnosed in our hospital were selected.

Methods: The clinical characteristics of 14 patients were statistically studied, and pathological specimens were analyzed by immunohistochemistry.

Results: We detected statistically significant difference in the expression of β-catenin (P = 0.000), glypican3 (P = 0.019), and hepar-1 (P = 0.007) between HAS cancer tissues and normal tissues. Furthermore, a significant correlation was found between the expression of β-catenin in HAS cancer tissue and normal tissue (Pearson correlation coefficient: 0.686, P = 0.007). Meanwhile, a significant correlation was observed between the expression of β-catenin and survival time (Spearman correlation coefficient= - 0.482, P = 0.003). However, we found the expression of β-catenin did not correlate with the tumor differentiation and size, age, gender, serum AFP levels, microinvasion, and metastasis (P > 0.05).

Conclusion: Our findings establish β-catenin as a useful marker that can distinguish HAS from CGA and may improve the early diagnosis to guide the appropriate and timely treatment of HAS patients.
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http://dx.doi.org/10.2174/0929867327666200522215607DOI Listing
May 2020

2SigFinder: the combined use of small-scale and large-scale statistical testing for genomic island detection from a single genome.

BMC Bioinformatics 2020 Apr 29;21(1):159. Epub 2020 Apr 29.

College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, 310018, China.

Background: Genomic islands are associated with microbial adaptations, carrying genomic signatures different from the host. Some methods perform an overall test to identify genomic islands based on their local features. However, regions of different scales will display different genomic features.

Results: We proposed here a novel method "2SigFinder ", the first combined use of small-scale and large-scale statistical testing for genomic island detection. The proposed method was tested by genomic island boundary detection and identification of genomic islands or functional features of real biological data. We also compared the proposed method with the comparative genomics and composition-based approaches. The results indicate that the proposed 2SigFinder is more efficient in identifying genomic islands.

Conclusions: From real biological data, 2SigFinder identified genomic islands from a single genome and reported robust results across different experiments, without annotated information of genomes or prior knowledge from other datasets. 2SigHunter identified 25 Pathogenicity, 1 tRNA, 2 Virulence and 2 Repeats from 27 Pathogenicity, 1 tRNA, 2 Virulence and 2 Repeats, and detected 101 Phage and 28 HEG out of 130 Phage and 36 HEGs in S. enterica Typhi CT18, which shows that it is more efficient in detecting functional features associated with GIs.
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http://dx.doi.org/10.1186/s12859-020-3501-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191778PMC
April 2020

Development of a 3Mut-Apex-Stabilized Envelope Trimer That Expands HIV-1 Neutralization Breadth When Used To Boost Fusion Peptide-Directed Vaccine-Elicited Responses.

J Virol 2020 06 16;94(13). Epub 2020 Jun 16.

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

HIV-1 envelope (Env) trimers, stabilized in a prefusion-closed conformation, can elicit humoral responses capable of neutralizing HIV-1 strains closely matched in sequence to the immunizing strain. One strategy to increase elicited neutralization breadth involves vaccine priming of immune responses against a target site of vulnerability, followed by vaccine boosting of these responses with prefusion-closed Env trimers. This strategy has succeeded at the fusion peptide (FP) site of vulnerability in eliciting cross-clade neutralizing responses in standard vaccine-test animals. However, the breadth and potency of the elicited responses have been less than optimal. Here, we identify three mutations (3mut), Met302, Leu320, and Pro329, that stabilize the apex of the Env trimer in a prefusion-closed conformation and show antigenically, structurally, and immunogenically that combining 3mut with other approaches (e.g., repair and stabilize and glycine-helix breaking) yields well-behaved clade C-Env trimers capable of boosting the breadth of FP-directed responses. Crystal structures of these trimers confirmed prefusion-closed apexes stabilized by hydrophobic patches contributed by Met302 and Leu320, with Pro329 assuming canonically restricted dihedral angles. We substituted the N-terminal eight residues of FP (FP8, residues 512 to 519) of these trimers with the second most prevalent FP8 sequence (FP8v2, AVGLGAVF) and observed a 3mut-stabilized consensus clade C-Env trimer with FP8v2 to boost the breadth elicited in guinea pigs of FP-directed responses induced by immunogens containing the most prevalent FP8 sequence (FP8v1, AVGIGAVF). Overall, 3mut can stabilize the Env trimer apex, and the resultant apex-stabilized Env trimers can be used to expand the neutralization breadth elicited against the FP site of vulnerability. A major hurdle to the development of an effective HIV-1 vaccine is the elicitation of serum responses capable of neutralizing circulating strains of HIV, which are extraordinarily diverse in sequence and often highly neutralization resistant. Recently, we showed how sera with 20 to 30% neutralization breadth could, nevertheless, be elicited in standard vaccine test animals by priming with the most prevalent N-terminal 8 residues of the HIV-1 fusion peptide (FP8), followed by boosting with a stabilized BG505-envelope (Env) trimer. Here, we show that subsequent boosting with a 3mut-apex-stabilized consensus C-Env trimer, modified to have the second most prevalent FP8 sequence, elicits higher neutralization breadth than that induced by continued boosting with the stabilized BG505-Env trimer. With increased neutralizing breadth elicited by boosting with a heterologous trimer containing the second most prevalent FP8 sequence, the fusion peptide-directed immune-focusing approach moves a step closer toward realizing an effective HIV-1 vaccine regimen.
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http://dx.doi.org/10.1128/JVI.00074-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307166PMC
June 2020

Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis.

Cancer Lett 2020 07 4;481:63-75. Epub 2020 Mar 4.

Liver Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, 02903, USA; Department of Internal Medicine, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. Electronic address:

To demonstrate multifaceted contribution of aspartate β-hydroxylase (ASPH) to pancreatic ductal adenocarcinoma (PDAC) pathogenesis, in vitro metastasis assay and patient derived xenograft (PDX) murine models were established. ASPH propagates aggressive phenotypes characterized by enhanced epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, extracellular matrix (ECM) degradation/remodeling, angiogenesis, stemness, transendothelial migration and metastatic colonization/outgrowth at distant sites. Mechanistically, ASPH activates Notch cascade through direct physical interactions with Notch1/JAGs and ADAMs. The ASPH-Notch axis enables prometastatic secretome trafficking via exosomes, subsequently initiates MMPs mediated ECM degradation/remodeling as an effector for invasiveness. Consequently, ASPH fosters primary tumor development and pulmonary metastasis in PDX models, which was blocked by a newly developed small molecule inhibitor (SMI) specifically against ASPH's β-hydroxylase activity. Clinically, ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stage PDAC. Relatively high levels of ASPH-Notch network components independently/jointly predict curtailed overall survival (OS) in PDAC patients (log-rank test, Ps < 0.001; Cox proportional hazards regression, P < 0.001). Therefore, ASPH-Notch axis is essential for propagating multiple-steps of metastasis and predicts prognosis of PDAC patients. A specific SMI targeting ASPH offers a novel therapeutic approach to substantially retard PDAC development/progression.
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http://dx.doi.org/10.1016/j.canlet.2020.02.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309190PMC
July 2020

VRC34-Antibody Lineage Development Reveals How a Required Rare Mutation Shapes the Maturation of a Broad HIV-Neutralizing Lineage.

Cell Host Microbe 2020 04 3;27(4):531-543.e6. Epub 2020 Mar 3.

Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD 20892, USA.

Rare mutations have been proposed to restrict the development of broadly neutralizing antibodies against HIV-1, but this has not been explicitly demonstrated. We hypothesized that such rare mutations might be identified by comparing broadly neutralizing and non-broadly neutralizing branches of an antibody-developmental tree. Because sequences of antibodies isolated from the fusion peptide (FP)-targeting VRC34-antibody lineage suggested it might be suitable for such rare mutation analysis, we carried out next-generation sequencing (NGS) on B cell transcripts from donor N123, the source of the VRC34 lineage, and functionally and structurally characterized inferred intermediates along broadly neutralizing and poorly neutralizing developmental branches. The broadly neutralizing VRC34.01 branch required the rare heavy-chain mutation Y33P to bind FP, whereas the early bifurcated VRC34.05 branch did not require this rare mutation and evolved less breadth. Our results demonstrate how a required rare mutation can restrict development and shape the maturation of a broad HIV-1-neutralizing antibody lineage.
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http://dx.doi.org/10.1016/j.chom.2020.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467872PMC
April 2020

Preclinical Development of a Fusion Peptide Conjugate as an HIV Vaccine Immunogen.

Sci Rep 2020 02 20;10(1):3032. Epub 2020 Feb 20.

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, MD, USA.

The vaccine elicitation of broadly neutralizing antibodies against HIV-1 is a long-sought goal. We previously reported the amino-terminal eight residues of the HIV-1-fusion peptide (FP8) - when conjugated to the carrier protein, keyhole limpet hemocyanin (KLH) - to be capable of inducing broadly neutralizing responses against HIV-1 in animal models. However, KLH is a multi-subunit particle derived from a natural source, and its manufacture as a clinical product remains a challenge. Here we report the preclinical development of recombinant tetanus toxoid heavy chain fragment (rTTHC) linked to FP8 (FP8-rTTHC) as a suitable FP-conjugate vaccine immunogen. We assessed 16 conjugates, made by coupling the 4 most prevalent FP8 sequences with 4 carrier proteins: the aforementioned KLH and rTTHC; the H. influenzae protein D (HiD); and the cross-reactive material from diphtheria toxin (CRM197). While each of the 16 FP8-carrier conjugates could elicit HIV-1-neutralizing responses, rTTHC conjugates induced higher FP-directed responses overall. A Sulfo-SIAB linker yielded superior results over an SM(PEG)2 linker but combinations of carriers, conjugation ratio of peptide to carrier, or choice of adjuvant (Adjuplex or Alum) did not significantly impact elicited FP-directed neutralizing responses in mice. Overall, SIAB-linked FP8-rTTHC appears to be a promising vaccine candidate for advancing to clinical assessment.
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http://dx.doi.org/10.1038/s41598-020-59711-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033230PMC
February 2020

Surveillance and management for serous cystic neoplasms of the pancreas based on total hazards-a multi-center retrospective study from China.

Ann Transl Med 2019 Dec;7(24):807

Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

Background: Serous cystic neoplasms (SCN) rarely have malignant potential, so accurate diagnosis of SCN is crucial for proper clinical management, especially to avoid unnecessary surgeries. However, the misdiagnosis of other pancreatic cystic neoplasm instead of SCN may highly increase the risk of malignancy in patients who receive no surgery.

Methods: Data from a total of 678 patients with pathologically confirmed to have SCN at sixteen institutions in China from January 1, 2006 to December 31, 2016 were retrieved to evaluate the malignancy risk of SCN.

Results: Among the 678 patients confirmed to have SCN with postoperative pathologic analysis, 649 patients (95.7%) had only one lesion and the average maximum diameter was 3.8±2.47 cm. Four patients were pathologically verified as having serous cystadenocarcinoma, so the SCN actual malignancy rate was 0.6%, while the mortality due to pancreatic surgery in these high-volume centers was nearly 0.2-2%. However, among the 99 SCN patients based on preoperative radiology, three were confirmed to have intraductal papillary mucinous neoplasms (IPMN), nine as mucinous cystic neoplasms (MCN), and four as solid pseudopapillary tumors (SPT) after postoperative pathological analysis. Thus, the total theoretical malignancy rate resulting from preoperative misdiagnosis was elevated to approximately 2.9%, higher than the risk of perioperative mortality.

Conclusions: When SCN can't be accurately distinguished from cystic tumors of pancreas, the malignant risk of cystic tumors may be higher than perioperative risk. However, if it can be diagnosed as SCN accurately, surgery can be avoided as well.
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http://dx.doi.org/10.21037/atm.2019.12.70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989871PMC
December 2019

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis.

J Exp Clin Cancer Res 2020 Jan 30;39(1):24. Epub 2020 Jan 30.

Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, NO. 301, Middle Yanchang Road, Jing'an District, Shanghai, 200072, China.

Background: Hepatocellular carcinoma (HCC) is a common primary malignant tumor which usually progresses to an advanced stage because of late diagnosis. Sorafenib (Sora) is a first line medicine for advanced stage HCC; however, it has been faced with enormous resistance. Simvastatin (Sim) is a cholesterol-lowering drug and has been reported to inhibit tumor growth. The present study aims to determine whether Sora and Sim co-treatment can improve Sora resistance in HCC.

Methods: The HCC cell line LM3 and an established Sora-resistant LM3 cell line (LM3-SR) were used to study the relationship between Sora resistance and aerobic glycolysis. Cell proliferation, apoptosis and glycolysis levels were analyzed by western blotting, flow cytometry analysis and biomedical tests. A xenograft model was also used to examine the effect of Sim in vivo. Detailed mechanistic studies were also undertaken by the use of activators and inhibitors, and lentivirus transfections.

Results: Our results demonstrated that the resistance to Sora was associated with enhanced aerobic glycolysis levels. Furthermore, LM3-SR cells were more sensitive to Sim than LM3 cells, suggesting that combined treatment with both Sora and Sim could enhance the sensitivity of LM3-SR cells to Sora. This finding may be due to the suppression of the HIF-1α/PPAR-γ/PKM2 axis.

Conclusions: Simvastatin can inhibit the HIF-1α/PPAR-γ/PKM2 axis, by suppressing PKM2-mediated glycolysis, resulting in decreased proliferation and increased apoptosis in HCC cells, and re-sensitizing HCC cells to Sora.
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http://dx.doi.org/10.1186/s13046-020-1528-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993409PMC
January 2020

HYAL-1-induced autophagy facilitates pancreatic fistula for patients who underwent pancreaticoduodenectomy.

FASEB J 2020 02 19;34(2):2524-2540. Epub 2019 Dec 19.

Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.

The main mechanism of hyaluronidase 1(HYAL-1) in the development of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD) was unknown. In this study, a comprehensive inventory of pre-, intra-, and postoperative clinical and biological data of two cohorts (62 pancreatic cancer [PCa] and 111 pancreatic ductal adenocarcinoma [PDAC]) which could induce POPF were retrospectively analyzed. Then, a total of 7644 genes correlated with HYAL-1 was predicted in PDAC tissues and the enriched pathway, kinase targets and biological process of those correlated genes were evaluated. Finally, a mouse pancreatic fistula (PF) model was first built and in vitro studies were performed to investigate the effects of HYAL-1 on PF progression. Our data indicated that preoperative serum HYAL-1 level, pancreatic fibrosis score, and pancreatic duct size were valuable factors for detecting POPF of Grade B and C. The serum HYAL-1 level of 2.07 mg/ml and pancreatic fibrosis score of 2.5 were proposed as the cutoff values for indicating POPF. The bioinformatic analysis and in vitro and in vivo studies demonstrated that HYAL-1 facilitates pancreatic acinar cell autophagy via the dephosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and signal transducers and activators of transcription 3 (STAT3) signaling pathways, which exacerbate pancreatic secretion and inflammation. In summary, the preoperative serum HYAL-1 was a significant predictor for POPF in patients who underwent PD. Tumor-induced HYAL-1 is one of core risk in accelerating PF and then promoting pancreatic secretion and acute inflammation response through the AMPK and STAT3-induced autophagy.
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http://dx.doi.org/10.1096/fj.201901583RDOI Listing
February 2020

Increasing carbon storage in subtropical forests over the Yangtze River basin and its relations to the major ecological projects.

Sci Total Environ 2020 Mar 18;709:136163. Epub 2019 Dec 18.

State Key Laboratory of Hydrology-Water Resources and Hydraulics Engineering, Hohai University, Nanjing 210098, China; Institute of Surface-Earth System Science, Tianjin University, Tianjin 300072, China. Electronic address:

Forest carbon stocks has an important role in the global carbon budget. Based on the satellite-observed and LPJ model simulated aboveground biomass carbon (ABC) data, the spatial and temporal changes of subtropical forest carbon storage in the Yangtze River basin and its relations to the climate variation and human activities were analyzed by using the methods of cumulative curve analysis and climate sensitivity analysis during 1993-2012. The results revealed that: (1) In general, the forest ABC increased obviously in the Yangtze River basin during the past 20 years, and the ABC rose from 2563.91 Tg C in 1993 to 2893.17 Tg C in 2012, with a growth rate of 12.84%. The higher ABC distribution was mainly concentrated in the Jialing River basin and Hanjiang River basin and the significantly increasing trends could be found in most area of the Yangtze River basin; (2) The forest ABC was sensitive to the changes of temperature and precipitation. When the temperature increases by 1 °C, the ABC in the Yangtze River basin will increase by 3.32%, while it will decrease by -6.12% when the precipitation increases by 10%; (3) The forest ABC growth rate had accelerated from 3.15% in 1993-2000 to 8.01% in 2001-2012. The cumulative curve of the forest ABC was generally higher than the temperature or the precipitation after 2000. The total areas induced by climate variation and human activities accounted for 30.5% and 52.59% with an increases in ABC by 67.52 Tg C and 188.74 Tg C from 1993 to 2012, respectively. The implementation of major forestry projects might be the main reason for the rapid increase of forest ABC in the Yangtze River basin. This study suggested human activities such as ecological projects might contribute to the accelerated greening trend and highlighted the pivotal role of subtropical forest ABC in the carbon budget in China.
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http://dx.doi.org/10.1016/j.scitotenv.2019.136163DOI Listing
March 2020

Aspartate β-hydroxylase promotes pancreatic ductal adenocarcinoma metastasis through activation of SRC signaling pathway.

J Hematol Oncol 2019 12 30;12(1):144. Epub 2019 Dec 30.

Liver Research Center, Rhode Island Hospital, Warren Alpert Medical School, Brown University, 55 Claverick Street, 4th Fl., Providence, RI, 02903, USA.

Background: Signaling pathways critical for embryonic development re-emerge in adult pancreas during tumorigenesis. Aspartate β-hydroxylase (ASPH) drives embryonic cell motility/invasion in pancreatic development/differentiation. We explored if dysregulated ASPH is critically involved in pancreatic cancer pathogenesis.

Methods: To demonstrate if/how ASPH mediates malignant phenotypes, proliferation, migration, 2-D/3-D invasion, pancreatosphere formation, immunofluorescence, Western blot, co-immunoprecipitation, invadopodia formation/maturation/function, qRT-PCR, immunohistochemistry (IHC), and self-developed in vitro metastasis assays were performed. Patient-derived xenograft (PDX) models of human pancreatic ductal adenocarcinoma (PDAC) were established to illustrate in vivo antitumor effects of the third-generation small molecule inhibitor specifically against ASPH's β-hydroxylase activity. Prognostic values of ASPH network components were evaluated with Kaplan-Meier plots, log-rank tests, and Cox proportional hazards regression models.

Results: ASPH renders pancreatic cancer cells more aggressive phenotypes characterized by epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, invadopodia formation/function as demonstrated by extracellular matrix (ECM) degradation, stemness (cancer stem cell marker upregulation and pancreatosphere formation), transendothelial migration (mimicking intravasation/extravasation), and sphere formation (mimicking metastatic colonization/outgrowth at distant sites). Mechanistically, ASPH activates SRC cascade through direct physical interaction with ADAM12/ADAM15 independent of FAK. The ASPH-SRC axis enables invadopodia construction and initiates MMP-mediated ECM degradation/remodeling as executors for invasiveness. Pharmacologic inhibition of invadopodia attenuates in vitro metastasis. ASPH fosters primary tumor development and pulmonary metastasis in PDX models of PDAC, which is blocked by a leading compound specifically against ASPH enzymatic activity. ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stages of PDAC. Expression profiling of ASPH-SRC network components independently/jointly predicts clinical outcome of PDAC patients. Compared to a negative-low level, a moderate-very high level of ASPH, ADAM12, activated SRC, and MMPs correlated with curtailed overall survival (OS) of pancreatic cancer patients (log-rank test, ps < 0.001). The more unfavorable molecules patients carry, the more deleterious prognosis is destinated. Patients with 0-2 (n = 4), 3-5 (n = 8), 6-8 (n = 24), and 9-12 (n = 73) unfavorable expression scores of the 5 molecules had median survival time of 55.4, 15.9, 9.7, and 5.0 months, respectively (p < 0.001).

Conclusion: Targeting the ASPH-SRC axis, which is essential for propagating multi-step PDAC metastasis, may specifically/substantially retard development/progression and thus improve prognosis of PDAC.
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http://dx.doi.org/10.1186/s13045-019-0837-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937817PMC
December 2019

Cell-in-Cell Phenomenon and Its Relationship With Tumor Microenvironment and Tumor Progression: A Review.

Front Cell Dev Biol 2019 3;7:311. Epub 2019 Dec 3.

Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.

The term cell-in-cell, morphologically, refers to the presence of one cell within another. This phenomenon can occur in tumors but also among non-tumor cells. The cell-in-cell phenomenon was first observed 100 years ago, and it has since been found in a variety of tumor types. Recently, increasing attention has been paid to this phenomenon and the underlying mechanism has gradually been elucidated. There are three main related process: cannibalism, emperipolesis, and entosis. These processes are affected by many factors, including the tumor microenvironment, mitosis, and genetic factors. There is considerable evidence to suggest that the cell-in-cell phenomenon is associated with the prognosis of cancers, and it promotes tumor progression in most situations. Notably, in pancreatic cancer, the cell-in-cell phenomenon is associated with reduced metastasis, which is the opposite of what happens in other tumor types. Thus, it can also inhibit tumor progression. Studies show that cell-in-cell structure formation is affected by the tumor microenvironment, and that it may lead to changes in cellular characteristics. In this review, we summarize the different cell-in-cell processes and discuss their role in tumor progression and how they are regulated by different mechanisms.
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http://dx.doi.org/10.3389/fcell.2019.00311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901391PMC
December 2019

Soluble urokinase plasminogen activator receptor associates with higher risk, advanced disease severity as well as inflammation, and might serve as a prognostic biomarker of severe acute pancreatitis.

J Clin Lab Anal 2020 Mar 27;34(3):e23097. Epub 2019 Nov 27.

Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.

Background: This study aimed to explore the potential of soluble urokinase plasminogen activator receptor (suPAR) as a biomarker for severe acute pancreatitis (SAP) risk prediction and disease management in SAP patients.

Methods: Totally 225 acute pancreatitis (AP) patients (including 75 SAP, 75 moderate-severe acute pancreatitis [MSAP], and 75 mild acute pancreatitis [MAP] patients) were recruited based on the Atlanta classification, and their serum samples were obtained within 24 hours after admission. Meanwhile, 75 health controls (HCs) were recruited with their serum samples collected at the enrollment. The serum suPAR was then detected using enzyme-linked immunosorbent assay.

Results: The suPAR level was increased in SAP patients compared with MSAP patients (P = .023), MAP patients (P < .001), and HCs (P < .001). Receiver operating characteristic (ROC) curve presented that suPAR could not only differentiate SAP patients from HCs (AUC: 0.920, 95%CI: 0.875-0.965) but also differentiate SAP patients from MSAP (AUC: 0.684, 95%CI: 0.600-0.769) and MAP patients (AUC: 0.855, 95%CI: 0.797-0.912). In SAP patients, suPAR was positively correlated with Ranson score (P < .001), acute physiology and chronic healthcare evaluation II score (P = .001), sequential organ failure assessment score (P < .001), and C-reaction protein (P = .002). Further ROC curve exhibited that suPAR (AUC: 0.806, 95%CI: 0.663-0.949) was of good value in predicting increased inhospital mortality of SAP patients.

Conclusion: Soluble urokinase plasminogen activator receptor is of good predictive value for SAP risk and may serve as a potential biomarker for disease severity, inflammation, and inhospital mortality in SAP patients.
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http://dx.doi.org/10.1002/jcla.23097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083411PMC
March 2020